Candidiasis represents the third leading cause of hospital-acquired bloodstream infections in the U.S. Candida albicans, the most commonly isolated human fungal pathogen, is associated with 50% of infections while several non-albicans Candida species (NACS), including Candida tropicalis and Candida parapsilosis, account for the remainder of cases. Only three major classes of antifungals are currently available for treatment and there is a significant demand for new and more effective therapies. A major virulence property of C. albicans is the ability to undergo a reversible morphological transition from yeast (single, oval budding cells) to filamentous (elongated cells attached end-to-end) form in response to a variety of host environmental cues. We have previously shown that constitutive high-level expression of UME6, a key transcriptional regulator of filamentous growth, is sufficient to promote C. albicans filamentation, tissue invasion and virulence in a mouse model of systemic candidiasis. Many NACS are believed to be less pathogenic, in part, because they do not filament as robustly as C. albicans and undergo filamentation in response to a far more limited set of environmental cues. We have recently demonstrated that expression of UME6 orthologs in C. tropicalis and C. parapsilosis is sufficient to drive significantly increased filamentation, as well as increased expression of several filament-specific genes. Surprisingly, however, we have found that in a mouse model of systemic candidiasis UME6 expression in both C. tropicalis and C. parapsilosis leads to a dramatic reduction in organ fungal burden and, eventually, clearance of the infection over time. These results challenge the current paradigm that certain NACS are less pathogenic due to reduced filamentation ability and suggest a novel hypothesis that filamentation in these species confers an evolutionary disadvantage during infection and is sufficient to elicit a protective host immune response. In order to address this hypothesis we will carry out experiments which are directed to achieve two specific aims: 1) identify, using transcriptional profiling, C. tropicalis and C. parapsilosis genes showing expression changes in response to UME6 induction and important for organ clearance. 2) Determine the ability of C. tropicalis and C. parapsilosis filamentation to reduce virulence and elicit a protective immune response during a systemic infection. More specifically, we will examine the global host immune profile in response to infection with C. tropicalis and C. parapsilosis UME6 expression strains and also determine the ability of UME6 expression to confer protection against secondary challenge with wild-type Candida species, including C. albicans. In addition to providing greater insight into the evolutionary relationship between filamentation and virulence in Candida species and challenging conventional views that C. albicans can be used as a model for the study of many NACS, these studies are also likely to provide information leading to the development of novel and more effective strategies to treat candidiasis.